tbuckley/cabot-search huggingface dataset:
Abstract 398: Tribbles 2 confers resistance to anti-androgenic therapy in prostate cancer via lineage switching
Authors: Jitender Monga, Indra Adrianto, Craig Rogers, Shirish Gadgeel, Dhananjay Chitale, Jagadananda Ghosh
Journal: Cancer Research (2022)

Abstract Background: About 33,000 men will die due to prostate cancer in the US in the year 2021. Prostate cancer initially responds to androgen receptor (AR) targeted therapies (e.g., enzalutamide, darolutamide). However, therapy-resistant, aggressive, lethal malignancy invariably develops for which no effective, targeted treatment options are available. Though failures of AR-targeted therapies remain as major cause for mortality among prostate cancer patients, molecular mechanisms underlying the emergence of resistance are still to be fully characterized. Methods: To understand the molecular basis of enzalutamide resistance, we developed a prostate cancer cell model to mimic the clinical conditions in enzalutamide-resistant disease. These cells were transcriptionally profiled for gene expression analysis by Illumina Hi-Seq whole genome gene-expression array. Hits were validated by RT-qPCR and Western blot. For clinical correlation, samples from enzalutamide treated prostate PDX models as well as surgical prostate tumors from patients were comprehensively analyzed. Role of new hits were determined by lentiviral shRNAs and analysis of cell viability, apoptosis, and downstream targets. Pro-cancer effects were analyzed by cell proliferation, invasion, and soft-agar colony formation. Results: We identified that the Tribbles 2 (TRIB2) pseudokinase is overexpressed in enzalutamide resistant prostate cancer (ERPC) cells. Elevated level of TRIB2 was also observed in enzalutamide treated PDX tumors in mice, and in prostate tumors from patients who were treated with enzalutamide. We found that TRIB2 protein level is especially higher in prostate cancer cells where the AR activity is low, or absent due to genetic changes. Forced overexpression of TRIB2 results in aggressive prostate cancer cell growth and makes the cells resistant to enzalutamide. Conversely, inhibition of TRIB2 by shRNA or chemical inhibitor decreases viability and re-sensitizes ERPC cells back to enzalutamide, suggesting that TRIB2 plays an important role as a driver in the resistance mechanism. Interestingly, TRIB2 downregulates luminal markers, but upregulates neuroendocrine markers via the master neuronal transcription factor, BRN2, and the reprogramming factor, SOX2. Inhibition of either BRN2 or SOX2 also re-sensitizes ERPC cells to enzalutamide. Conclusion: These findings suggest that TRIB2 confers resistance to enzalutamide therapy through lineage switching from luminal to neuroendocrine type, involving BRN2 and SOX2. Citation Format: Jitender Monga, Indra Adrianto, Craig Rogers, Shirish Gadgeel, Dhananjay Chitale, Jagadananda Ghosh. Tribbles 2 confers resistance to anti-androgenic therapy in prostate cancer via lineage switching [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 398.
Abstract 1101: CTNNB1 mutation can mediate resistance to EGFR, ALK and KRAS targeted therapies
Authors: Anurima Majumder, Benjamin S. Meyer, J Kevin Hicks, Theresa A. Boyle, Eric B. Haura
Journal: Cancer Research (2022)

Abstract Resistance to targeted therapy remains an ongoing and elusive challenge in lung cancer. β-Catenin (CTNNB1) mutations have been reported in lung cancer patients, often co-occurring with known oncogenic drivers such as rearranged ALK, and mutant EGFR and KRAS. Oncogenic CTNNB1 mutations result in aberrant accumulation of the encoded β-catenin protein and may cause resistance to targeted therapy. However, different CTNNB1 mutations may activate β-catenin differentially and thereby have varying phenotypic effects. A CTNNB1 T41A mutation was identified in donated lung cancer tissue from a patient with a clinical history of an EGFR exon 20 insertion. To investigate the functional significance of this mutation, CTNNB1 T41A was transduced into an EGFR-mutated cell line (HCC827) and one cell line harboring ALK translocation (STE1). Response to EGFR and ALK targeted therapy was then compared in the GFP-transduced control cell lines versus the CTNNB1 T41A transduced cell lines to assess for effects of this CTNNB1 mutation on targeted therapy. Both HCC827 and STE1 cells harboring the CTNNB1 T41A mutation were more resistant to EGFR and ALK targeted therapy than the control cell lines. Since, different CTNNB1 mutations may exert different phenotypic effects, the CTNNB1 mutation spectrum was analyzed in lung cancer patients at the Moffitt Cancer Center. Mutations in 19 unique residues of CTNNB1 (D32, S33, G34, S37, T41, S45, A215, C419, S29, G757, K335, N287, Q72, R151, R710, S352, S681, V62 and W383) were detected in 50 lung cancer patients. Of these, 23 had some type of EGFR abnormality that co-existed with the CTNNB1 mutation while others had ROS1, RET, BRAF, NTRK3, ALK or KRAS mutations. The most frequent Exon 3 hotspot CTNNB1 mutations (at residues D32, S33, G34, S37, and S45) were chosen for further analysis wherein these mutations were transduced into HCC827, STE1 and two KRAS mutant cell lines (H358 and LU65) to assess their ability to drive resistance to EGFR, ALK and KRAS targeted therapies in ongoing studies. Our data shows that CTNNB1 mutations can cause resistance to EGFR, ALK and KRAS inhibitor therapy to different extents. Hence, further investigation of the mechanism of action of these beta-catenin mutations and the ability of beta-catenin/other inhibitors to reverse resistance is needed. This data also suggests that CTNNB1 may be an important co-occurring alteration in the context of development of resistance to targeted therapy and should be included in comprehensive clinical genetic testing panels. Citation Format: Anurima Majumder, Benjamin S. Meyer, J Kevin Hicks, Theresa A. Boyle, Eric B. Haura. CTNNB1 mutation can mediate resistance to EGFR, ALK and KRAS targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1101.
Abstract 3607: A novel adjunctive LAT-activating CAR T (ALA-CART) cell platform demonstrates enhanced antigen sensitivity and eradication of antigen-low leukemia
Authors: Catherine Pham-Danis, Lillie Leach, Christopher Ebmeier, M. Eric Kohler
Journal: Cancer Research (2022)

Abstract CAR T cells have demonstrated clinical success in malignancies that are refractory to standard therapies; however, preclinical and clinical studies have demonstrated that CAR T cell efficacy is greatly reduced in settings of low levels of target antigen. This was exemplified in a clinical trial of CD22-directed CAR T cells where despite inducing complete remissions in &amp;gt;70% of patients, post-CAR relapses occurred in the majority of patients, driven by decreased expression of CD22 below the threshold required for adequate CAR T cell activation. To address this limitation of CAR T cells, we investigated the mechanism underlying suboptimal CAR responses to low levels of antigen. Using a SILAC/mass spectrometry approach, we performed global phosphoproteomics to examine CAR T cell signal transduction in response to high- and low-levels of CD22 antigen. Low levels of CD22 antigen resulted in decreased utilization of several canonical T cell signaling pathways in CAR T cells. We hypothesized that LAT, a scaffolding protein integral to the T cell signalosome, was inefficiently utilized in response to low levels of antigen. Indeed, while signaling events proximal to LAT, such as Zap70, were unaffected by CD22 antigen density, phosphorylation of LAT at multiple activating residues decreased in response to stimulation with CD22-low leukemia cells. To overcome the inefficient LAT activation by low levels of antigen, we designed a bicistronic construct consisting of a clinically active 2nd generation CD22-BBz CAR along with a novel Adjunctive LAT Activating CAR incorporating the intracellular signaling domain of LAT (ALA-CART). ALA-CART cells expressed both CARs on the surface and demonstrated enhanced phosphorylation of LAT and PLCγ in response to CD22-low leukemia cells. In xenograft models, ALA-CART cells completely eradicated CD22-low leukemia, significantly extending survival of mice in comparison to the standard CD22-BBz CAR which only modestly slowed leukemia progression. Additionally, in mice engrafted with leukemia expressing WT-levels of CD22, we found the persistence of ALA-CART cell was significantly enhanced relative to standard CD22-BBz CAR T cells. Thus, by identifying deficits in CAR signaling, we rationally designed the ALA-CART platform to target antigen-low cells, overcoming a mechanism of resistance to standard CAR therapies with the potential to improve outcomes of patients receiving CAR therapies. Citation Format: Catherine Pham-Danis, Lillie Leach, Christopher Ebmeier, M. Eric Kohler. A novel adjunctive LAT-activating CAR T (ALA-CART) cell platform demonstrates enhanced antigen sensitivity and eradication of antigen-low leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3607.
Abstract 6386: Phosphomimetic Dicer rewires glutamine metabolism and gemcitabine resistance in pancreatic ductal adenocarcinoma
Authors: Ching-Feng Chiu, Ji Min Park, Yu-Shiuan Shen, Chia-Ying Lin, Tung-Wei Hsu, Yen-Hao Su, Hsin-An Chen
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy that shows high cancer-mortality and poor prognosis, in the absence of obvious symptoms and biomarkers for early diagnosis. Gemcitabine is a type of chemotherapy drug which commonly used to treat PDAC, however, the rapid acquisition of resistance to gemcitabine treatment has been observed in many of PDAC patients. The miRNA-producing enzymes Dicer is crucial for the maturation of miRNAs, and we found previously that ERK/Sp1 signaling transactivate both gene and protein expressions of Dicer, leading an acquisition of gemcitabine resistance in pancreatic cancer cells both in vitro and in vivo. In this study, we further identified that phosphomimetic S1016E of Dicer may regulate miRNAs maturation, resulting an imbalance of glutaminase (GLS) and glutamine synthetase (GS/GLUL). Metabolism analysis revealed that gemcitabine-resistant PANC-1 (PANC-1/GEM) cells have high glutamine dependence and GLS/GLUL ratio. Our study suggests that phosphomimetic Dicer S1016E plays a critical role in glutamine metabolism reprogramming and gemcitabine resistance of pancreatic cancer. Citation Format: Ching-Feng Chiu, Ji Min Park, Yu-Shiuan Shen, Chia-Ying Lin, Tung-Wei Hsu, Yen-Hao Su, Hsin-An Chen. Phosphomimetic Dicer rewires glutamine metabolism and gemcitabine resistance in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6386.
Abstract 5700: Increasing efficacy of iBET-151, a small molecule inhibitor of BET protein in combination with paclitaxel in gastric cancer
Authors: Sun Kyoung Kang, Sang Woo Cho, Woo Sun Kwon, Tae Soo Kim, Hyun Cheol Chung, Sun Young Rha
Journal: Cancer Research (2022)

Abstract Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), which contributes to the development and progression of GC. BRD4 is one of the leaders for epigenetic regulation and is known to regulate the expression of oncogenes such as c-MYC, BCL-2, and CDK4. In a previous study, we evaluated the efficacy of iBET-151 in a large panel of GC cell lines and xenograft mouse models. We found that iBET-151 showed a modest growth-inhibitory effect in GC cells. Recent report showed, lowering the expression of BCL-2 and BCL-xL, which are the targets of BRD4, induces sensitivity to paclitaxel, frequently used antimitotic agent in GC. Therefore, we evaluate iBET-151 plus paclitaxel as a new combination treatment regimen for GC. The synergistic effect and possible mechanisms of iBET-151 with paclitaxel were evaluated in 49 GC cell lines or 10 GC organoids using cell proliferation assay, flow cytometry, western blotting, colony formation, and migration assays. We found that the addition of iBET-151 increased the sensitivity to paclitaxel alone treatment from 15% to 50% in approximately 70% (34/49) of GC cells. iBET-151 plus paclitaxel significantly promoted cell-cycle arrest at G1 or G2/M phase and increased sub-G1 phase and cleaved PARP expression, which correlates to increased cell death. Also, combined treatment suppressed c-Myc, Bcl-2, and Bcl-xL expression in AGS, YCC-1, YCC-32, and YCC-34. We found BET proteins were overexpressed in most patient-derived GC organoids whereas c-Myc, BCL-2, and BCL-xL were expressed at variable levels. We observed that there was a synergistic growth inhibition in 6 out of 10 (60%) organoids. The data suggests iBET-151 and paclitaxel have a synergistic effect not only in GC cell lines but also in GC organoids. In summary, our data show the combination of iBET-151 and paclitaxel resulted in markedly higher anti-tumor effects compared with either treatment alone for GC. With further studies to validate the efficacy and biomarker explorations, the combination of iBET-151 and paclitaxel represents a promising therapeutic strategy in GC. Citation Format: Sun Kyoung Kang, Sang Woo Cho, Woo Sun Kwon, Tae Soo Kim, Hyun Cheol Chung, Sun Young Rha. Increasing efficacy of iBET-151, a small molecule inhibitor of BET protein in combination with paclitaxel in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5700.
Abstract LB537: CDK4/6 inhibition enhances oncolytic efficacy on refractory glioblastoma by potentiating tumor-selective cell killing and T cell activation
Authors: Deyin Guo, Fan Xing, Jingshu Xiao, Jiaming liang
Journal: Cancer Research (2022)

Abstract Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor. Although oncolytic virus (OV) therapy has been proposed as a potential approach to treat GBM, the resistance is frequently observed because GBM cells are usually nonpermissive to OV. Here, we describe a dual-step drug screen for identifying chemical enhancers of oncolytic virus in GBM. An inhibitor of the cyclin-dependent kinases 4/6 (CDK4/6) was identified as the top enhancer from 1416 FDA-approved drugs, selectively increasing potency of the two OV strains, including VSVΔ51 and Zika virus. Mechanistically, CDK4/6 inhibition promoted the autophagic degradation of MAVS, resulting in impaired antiviral responses and enhanced tumor-selective replication of VSVΔ51 in vitro and in vivo. CDK4/6 inhibition cooperated with VSVΔ51 to induce severe DNA damage stress, leading to the amplification of oncolysis. In GBM xenograft models, combination treatment of CDK4/6 inhibitor and VSVΔ51 significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice. Further investigation revealed that CDK4/6 inhibitor and VSVΔ51 synergistically induced the immunogenic cell death and boosted the anti-tumor immunity. Together, our study features a promising approach of treating aggressive GBM through the combination of CDK4/6 inhibitor with OV. Citation Format: Deyin Guo, Fan Xing, Jingshu Xiao, Jiaming liang. CDK4/6 inhibition enhances oncolytic efficacy on refractory glioblastoma by potentiating tumor-selective cell killing and T cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB537.
High efficacy of glecaprevir/pibrentasvir for HCV-infected individuals with active drug use
Authors: Alejandro Gonzalez-Serna, Juan Macias, Anaïs Corma-Gomez, Francisco Tellez, Josep Cucurull, Luis M Real, Rafael Granados, Antonio Rivero-Juarez, José Hernandez-Quero, Dolores Merino, Rosario Palacios, Maria José Rios, Antonio Collado, Juan A. Pineda
Journal: Journal of Infection (2022)
Effectiveness of COVID-19 Viral Vector Ad.26.COV2.S Vaccine and Comparison with mRNA Vaccines in Cirrhosis
Authors: Binu V John, A Sidney Barritt, Andrew Moon, Tamar H Taddei, David E Kaplan, Bassam Dahman, Akash Doshi, Yangyang Deng, Natalie Mansour, George Ioannou, Paul Martin, Hann-Hsiang Chao
Journal: Clinical Gastroenterology and Hepatology (2022)
Abstract 3219: Changes and intra-individual reliability in computed tomography image-assessed adiposity and skeletal muscles areas after breast cancer surgery
Authors: Livingstone Aduse-Poku, Dheeraj Gopireddy, Mauricio Henandez, Chandana Lall, Joel Divaker, Sara Falzarano, Shahla Masood, Weizhou Zhang, Susmita Datta, Jiang Bian, Ting-Yuan David Cheng
Journal: Cancer Research (2022)

Abstract Background: Levels of adiposity and skeletal muscles are prognostic indicators in breast cancer patients; however, data are limited on temporal changes in body composition, particularly in different densities of muscles, before and after mastectomy. Objectives: We examined the change in CT-assessed adipose tissue and different density of skeletal muscle areas using a high-resolution segmentation method in breast cancer patients before and after surgery. Methods: This study included 50 newly-diagnosed breast cancer patients who had taken CT scans before and after surgery. We analyzed their third lumbar (L3) CT images to measure the areas of adipose tissue and five-level (from very-high-density to very-low-density) skeletal muscle components. We assessed mean and percent changes in areas using paired t-test and calculated the intra-class correlation (ICC). Results: Patients’ mean age at diagnosis was 58.3 (SD=12.5) years. The mean duration between scans was 591 (SD=537) days. There was a significant decrease in the areas of subcutaneous adipose tissue (mean change= -36.17 cm2, 11.72% decrease, p=0.029), total adipose tissue (mean change= -45.64 cm2, 10.18% decrease, p=0.032), and very-high-density muscle (mean change= -0.37 cm2, 11.08% decrease, p=0.010). The ratio of total adipose tissue and total skeletal muscle decreased from 3.67 to 3.32 after surgery (mean change= -0.36, 9.81% decrease, p=0.061). There was a strong correlation in adipose tissues and skeletal muscle areas of pre-and post-surgery scans taken within 3 years apart (ICC=0.802 to 0.999, all p&amp;lt;0.05), but the correlations were attenuated in scans taken &amp;gt;3 years apart (ICC = -0.055 to 0.738, all p&amp;gt;0.05). Conclusion: In this sample of breast cancer patients who have undergone surgery, there was a significant decrease in subcutaneous adipose tissues, total adipose tissues, and very-high-density muscle areas over time. Body composition assessed by CT images is reliable for a 3- year period involving breast cancer surgery. These findings serve as a baseline for prospective studies examining the impact of these changes on breast cancer outcomes. Keywords: Adipose tissue, skeletal muscle, computed tomography scans, breast cancer, surgery Citation Format: Livingstone Aduse-Poku, Dheeraj Gopireddy, Mauricio Henandez, Chandana Lall, Joel Divaker, Sara Falzarano, Shahla Masood, Weizhou Zhang, Susmita Datta, Jiang Bian, Ting-Yuan David Cheng. Changes and intra-individual reliability in computed tomography image-assessed adiposity and skeletal muscles areas after breast cancer surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3219.
Abstract CT206: EVT801, a novel selective VEGFR-3 inhibitor targeting tumor angiogenesis, started enrollment for its phase I first-in-human study
Authors: Carlos Gomez roca, Philippe Cassier, Marie Mandron, Myriam Estrabaut, Nathalie Delesque-Touchard, Adam C. Smith, Amy Klawitter, Leesa Gentry, Pierre Fons, Michael R. Paillasse, Lise Davenne, Michael Fitzgerald, James Garner, Jean-Pierre Delord
Journal: Cancer Research (2022)

Abstract Introduction: EVT801 is a highly selective, orally available VEGFR3 inhibitor that strongly inhibits angiogenesis without inducing hypoxia, considered one of the main causes of cancer-associated immunosuppression. EVT801 has shown compelling single agent efficacy in multiple in vivo models. In addition, combination of EVT801 and Immune Checkpoint Therapy (ICT) agents shows additive effects, and thus holds promise for combination treatment without induction of hypoxia-induced-immunosuppression. A phase I clinical trial is underway. Methods: The phase I trial will consist of two sequential stages. During the first stage, EVT801 will be administered to patients with advanced solid tumors in a multiple ascending dose study using an accelerated 3+3 design (1 patient per dose until grade 2 toxicities are observed) in up to 48 patients in 8 dose levels. The primary objective is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Stage 2 will focus on validation of this RP2D in two 6-patient cohorts diagnosed with soft tissue sarcoma or renal cell carcinoma. These patients will participate in intensive analyses involving several biomarkers to better understand the pharmacological activity of the drug. A potential third stage, consisting of a multiple ascending dose evaluation of the combination of EVT801 with immuno-oncology drugs, may be added to the ongoing trial, pending further technical discussions with physicians and regulators. In addition to conventional measures of safety, tolerability, efficacy, and pharmacokinetics, the phase I study will employ a rich suite of histological, immunological, and radiological biomarkers to provide early insights into the activity of EVT801. Citation Format: Carlos Gomez roca, Philippe Cassier, Marie Mandron, Myriam Estrabaut, Nathalie Delesque-Touchard, Adam C. Smith, Amy Klawitter, Leesa Gentry, Pierre Fons, Michael R. Paillasse, Lise Davenne, Michael Fitzgerald, James Garner, Jean-Pierre Delord. EVT801, a novel selective VEGFR-3 inhibitor targeting tumor angiogenesis, started enrollment for its phase I first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT206.